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https://hdl.handle.net/2440/72923
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Type: | Journal article |
Title: | Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile |
Author: | Parker, W. Ho, M. Scott, H. Hughes, T. Branford, S. |
Citation: | Blood, 2012; 119(10):2234-2238 |
Publisher: | Amer Soc Hematology |
Issue Date: | 2012 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | Wendy T. Parker, Musei Ho, Hamish S. Scott, Timothy P. Hughes and Susan Branford |
Abstract: | Specific imatinib-resistant BCR-ABL1 mutations (Y253H, E255K/V, T315I, F317L, and F359V/C) predict failure of second-line nilotinib or dasatinib therapy in patients with chronic myeloid leukemia; however, such therapy also fails in approximately 40% of patients in the chronic phase of this disease who do not have these resistant mutations. We investigated whether sensitive mutation analysis could identify other poor-risk subgroups. Analysis was performed by direct sequencing and sensitive mass spectrometry on 220 imatinib-resistant patients before they began nilotinib or dasatinib therapy. Patients with resistant mutations by either method (n = 45) were excluded because inferior response was known. Of the remaining 175 patients, 19% had multiple mutations by mass spectrometry versus 9% by sequencing. Compared with 0 or 1 mutation, the presence of multiple mutations was associated with lower rates of complete cytogenetic response (50% vs 21%, P = .003) and major molecular response (31% vs 6%, P = .005) and a higher rate of new resistant mutations (25% vs 56%, P = .0009). Sensitive mutation analysis identified a poor-risk subgroup (15.5% of all patients) with multiple mutations not identified by standard screening. |
Keywords: | Humans Benzamides Piperazines Pyrimidines Thiazoles Fusion Proteins, bcr-abl Protein Kinase Inhibitors Sequence Analysis, DNA DNA Mutational Analysis Drug Resistance, Neoplasm Mutation Mass Spectrometry Leukemia, Myelogenous, Chronic, BCR-ABL Positive Imatinib Mesylate Dasatinib |
Rights: | Copyright © 2012 by American Society of Hematology |
DOI: | 10.1182/blood-2011-08-375535 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/565170 |
Published version: | http://dx.doi.org/10.1182/blood-2011-08-375535 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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